The goal of these studies is to elucidate the mechanisms that regulate major histocompatibility complex (MHC) class II (Ia) gene expression. Class II gene expression is regulated in terms of tissue specificity, stage of development and in response to external stimuli. It has been determined that the regulation of MHC class II gene expression occurs at the level of transcription. We have recently defined several regulatory elements and DNA binding factors for class n genes. We have focused on a novel nuclear binding protein, Complex A, whose presence correlates with class II MHC expression. Our data support the hypothesis that the presence of Complex A plays a critical role in class II gene transcription. To determine the role of Complex A in class II gene expression, we will first determine the structure and function of Complex A in human class II gene expression. Second, to further analyze Complex A, we will exploit the correlation between Complex A and a family of yeast transcription factors. Finally, in order to characterize proteins which regulate class II expression, we will use a functional complementation strategy to isolate cDNA clones which restore MHC class II expression to class II deficient cells.